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With the advent of virally suppressive antiretroviral therapy (ART), life expectancy for persons with human immunodeficiency virus (HIV) with access to ART now approaches that of the general population. As persons with HIV age, noninfectious comorbidities occur more frequently compared with persons without HIV. Such comorbidities are likely to affect cognitive health, which may also be affected by lifestyle factors that may differ in persons with HIV. At the National Institutes of Health–supported meeting on Biotypes of Central Nervous System (CNS) Complications in persons with HIV, a session was devoted to early HIV treatment, noninfectious comorbidities, and aging as each pertains to cognitive health. Areas of consideration included acute and early HIV infection (presentation by Phillip Chan), drugs of abuse (Scott Letendre), stroke and cerebrovascular disease (Felicia Chow), mental health (John Joska), and aging (Julian Falutz). These presentations were followed by a discussion session led by Woody Lin, Jose A. Muñoz-Moreno, Paola Cinque, and Jeff Taylor. Alan Winston and Bruce Brew chaired the meeting with Jasmini Alagaratnam and Htein Linn Aung acting as rapporteurs. Here we present the main topics covered in the presentations, and the associated discussions highlighting knowledge gaps and future directions.

People living with HIV (PLWH) often have worse health outcomes compared to HIV-uninfected individuals. We characterized PLWH followed at a tertiary care clinic in Montreal who acquired COVID-19 and described their outcomes during the first wave of the pandemic. A retrospective chart review was performed for PLWH followed at the Chronic Viral Illness Service with a positive COVID-19 nasopharyngeal PCR or symptoms suggestive of COVID-19 between 1 March and 15 June 2020. Data on demographics, socioeconomic status, co-morbidities and severity of COVID-19 and outcomes were extracted. Of 1702 individuals, 32 (1.9%) had a positive COVID-19 test (n = 24) or symptoms suspicious for COVID-19 (n = 3). Median age was 52 years [IQR 40, 62]. Nearly all (97%) earned $34,999 Canadian dollars or less. Eleven (34%) individuals worked in long-term care (LTC) homes while 5 (6%) lived in LTC homes. Median CD4 count was 566 cells/mm3 [347, 726] and six had detectable plasma HIV viral loads. Median duration of HIV was 17 years [7, 22] and 30 individuals had been prescribed antiretroviral therapy. Five persons were asymptomatic. Of symptomatic persons, 21 (12%), 1 (4%) and 3 (12%) individuals had mild, moderate and severe disease, respectively. Three individuals died with COVID-19. In one case, the cause of death was due to COVID-19, whereas in the other two cases, the individuals died with positive COVID-19 test results but the immediate cause of death is unclear. PLWH who tested positive for COVID-19 had low socioeconomic status and had employment or living conditions that put them at high risk. PLWH may be disproportionately impacted by the social determinants of health which predispose them to COVID-19.

OBJECTIVES Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density = smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PWH), on fat density. DESIGN Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PWH were included if they had either a clinical response to tesamorelin (VAT decrease ≥8%, ≈70% of participants) or were placebo-treated. METHODS CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader. RESULTS Participants (193 responders, 148 placebo) were 87% male and 83% white. Baseline characteristics were similar across arms, including VAT (-91 HU both arms, P = 0.80) and SAT density (-94 HU tesamorelin, -95 HU placebo, P = 0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only [VAT: +6.2 (8.7) HU tesamorelin, +0.3 (4.2) HU placebo, P

Background Cardiovascular and liver disease are main causes of death in people with human immunodeficiency virus (HIV) (PWH). In HIV-uninfected patients, nonalcoholic fatty liver disease (NAFLD) is associated with incident metabolic complications. We investigated the effect of NAFLD on development of metabolic comorbid conditions in PWH. Methods We included PWH undergoing a screening program for NAFLD using transient elastography. NAFLD was defined as a controlled attenuation parameter ≥248 dB/m with exclusion of other liver diseases. Incident diabetes, hypertension, dyslipidemia, and chronic kidney disease were investigated using survival analysis and Cox proportional hazards. Results The study included 485 HIV-monoinfected patients. During a median follow-up of 40.1 months (interquartile range, 26.5–50.7 months), patients with NAFLD had higher incidences of diabetes (4.74 [95% confidence interval, 3.09–7.27] vs 0.87 [.42–1.83] per 100 person-years) and dyslipidemia (8.16 [5.42–12.27] vs 3.99 [2.67–5.95] per 100 person-years) than those without NAFLD. With multivariable analysis, NAFLD was an independent predictor of diabetes (adjusted hazard ratio, 5.13; 95% confidence interval, 2.14–12.31) and dyslipidemia (2.35; 1.34–4.14) development. Conclusions HIV-monoinfected patients with NAFLD are at higher risk of incident diabetes and dyslipidemia. Early referral strategies and timely management of metabolic risk may improve outcomes.

OBJECTIVES: Although weight gain on ART is common, the long-term trajectory of and factors affecting increases in fat mass in people living with HIV are not well described. METHODS: Men and women living with HIV in the Modena HIV Metabolic Clinic underwent DXA scans every 6–12 months for up to 10 years (median 4.6 years). Regression modelling in both combined and sex-stratified models determined changes in and clinical factors significantly associated with trunk and leg fat mass over the study period. RESULTS: A total of 839 women and 1759 men contributed two or more DXA scans. The baseline median age was 44 years and BMI 22.9 kg/m(2); 76% were virologically suppressed on ART at baseline. For both sexes, trunk and leg fat consistently increased over the study period, with mean yearly trunk and leg fat gain of 3.6% and 7.5% in women and 6.3% and 10.8% in men, respectively. In multivariate analysis, factors associated with greater fat mass included female sex, per-year ART use (specifically tenofovir disoproxil fumarate and integrase strand transfer inhibitor therapy), per-unit BMI increase, no self-reported physical activity and CD4 nadir

Objectives The reported prevalence of chronic obstructive pulmonary disease (COPD) in people living with HIV (PLWHIV) varies widely. Our objective was to estimate the prevalence of airflow obstruction and COPD in unselected PLWHIV and identify characteristics that increase the risk of nonreversible airflow obstruction in order to guide case finding strategies for COPD. Methods All adults attending the Chronic Viral Illness Service were invited to participate in the study, regardless of smoking status or history of known COPD/asthma. Individuals underwent spirometric testing both before and after use of a salbutamol bronchodilator. Airflow obstruction was defined as forced expiratory volume in 1 s (FEV 1)/forced vital capacity (FVC) < 0.7 post‐bronchodilation, whereas COPD was defined as FEV 1/FVC < 0.7 post‐bronchodilation and Medical Research Council (MRC) score > 2. Multivariate logistic regression was used to evaluate risk factors associated with airflow obstruction, reported as adjusted odds ratios (aORs). Results Five hundred and three participants successfully completed spirometry testing. The median (Q1; Q3) age was 52 (44; 58) years. The median (Q1; Q3) CD4 count was 598 (438; 784) cells/μL and the median (Q1; Q3) nadir CD4 count was 224 (121; 351) cells/μL. There were 119 (24%) current smokers and 145 (29%) former smokers. Among those screened, 54 (11%) had airflow obstruction whereas three (1%) of the participants had COPD. Factors that were associated with airflow obstruction included a history of smoking [aOR 2.2; 95% confidence interval (CI) 1.1; 4.7], older age (aOR 1.6; 95% CI 1.2; 2.2), and lower CD4 count (aOR 0.8; 95% CI 0.7; 1.0). Conclusions Airflow obstruction was relatively uncommon. Our findings suggest that PLWHIV who are ≥50 years old, smokers and those with nadir CD4 counts ≤ 200 cells/μL could be targeted to undergo spirometry to diagnose chronic airflow obstruction.

Purpose of review Older adults account for the majority of people with HIV (PWH) in high-income countries and have increasingly complex clinical profiles related to premature aging. Frailty is an important geriatric syndrome affecting a minority of PHW. Frailty negatively affects PHW's clinical status and quality of life. This review will update care providers on the current state of frailty that limits the healthspan of PWH. Recent findings Ongoing low-level HIV replication in treated PWH leads to immune activation and chronic inflammation contributing to the destabilization of normally autoregulated physiologic systems in response to environmental and biologic challenges characteristic of frailty. Understanding these underlying mechanisms will determine potential intervention options. Potentially reversible risk factors that promote progression to and reversion from the dynamic state of frailty are being studied and will help prevent frailty. Simple assessment tools and treatment strategies for frailty are being adapted for aging PWH. Summary Insight into underlying biologic mechanisms and adapting proven geriatric principles of interdisciplinary care will inform the healthy aging of PWH.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Early in the HIV epidemic, lipodystrophy, characterized by subcutaneous fat loss (lipoatrophy), with or without central fat accumulation (lipohypertrophy), was recognized as a frequent condition among people living with HIV (PLWH) receiving combination antiretroviral therapy. The subsequent identification of thymidine analogue nucleoside reverse transcriptase inhibitors as the cause of lipoatrophy led to the development of newer antiretroviral agents; however, studies have demonstrated continued abnormalities in fat and/or lipid storage in PLWH treated with newer drugs (including integrase inhibitor-based regimens), with fat gain due to restoration to health in antiretroviral therapy-naive PLWH, which is compounded by the rising rates of obesity. The mechanisms of fat alterations in PLWH are complex, multifactorial and not fully understood, although they are known to result in part from the direct effects of HIV proteins and antiretroviral agents on adipocyte health, genetic factors, increased microbial translocation, changes in the adaptive immune milieu after infection, increased tissue inflammation and accelerated fibrosis. Management includes classical lifestyle alterations with a role for pharmacological therapies and surgery in some patients. Continued fat alterations in PLWH will have an important effect on lifespan, healthspan and quality of life as patients age worldwide, highlighting the need to investigate the critical uncertainties regarding pathophysiology, risk factors and management. HIV and antiretroviral therapy-related fat alterations are frequent in people living with HIV and include fat loss, fat gain and obesity. This Primer discusses the changing epidemiology, mechanisms, diagnosis and treatment of these alterations.

Objectives: Current guidelines recommend use of a diagnostic algorithm to assess disease severity in cases of suspected nonalcoholic fatty liver disease (NAFLD). We applied this algorithm to HIV-monoinfected patients. Methods: We analysed three prospective screening programmes for NAFLD carried out in the following cohorts: the Liver Disease in HIV (LIVEHIV) cohort in Montreal, the Modena HIV Metabolic Clinic (MHMC) cohort and the Liver Pathologies in HIV in Palermo (LHivPa) cohort. In the LIVEHIV and LHivPa cohorts, NAFLD was diagnosed if the controlled attenuation parameter (CAP) was ≥248dB/m; in the MHMC cohort, it was diagnosed if the liver/spleen Hounsfield unit (HU) ratio on abdominal computerized tomography scan was

The increased survival of treated people living with HIV (PLWH) represents a tremendous accomplishment. However, this has not been accompanied by uniform improvements in quality of life. Many PLWH prematurely develop age-related complications and traditional geriatric syndromes, including frailty. This is a potentially reversible state of vulnerability to adverse outcomes. Its operationalization remains challenging. The most commonly used tools, the frailty phenotype and the frailty index, have their advantages and limitations, but predict similar poor outcomes. Yeoh et al. applied both metrics, and a simpler construct, the Edmonton Frail Scale, to a population of Australian PLWH. Although the prevalence of frailty was generally similar to that in other settings, distinct differences occurred between the tools. This paper adds to the literature on this serious condition in this already vulnerable population. Further research is needed before consensus is reached on how to reliably and simply diagnose frailty in PLWH.

OBJECTIVE Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). DESIGN AND METHODS We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period. RESULTS At baseline, VAT was positively associated with ALT (P = 0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30 U/l, VAT responders experienced greater reductions in ALT (-8.9 ± 22.6 vs. 1.4 ± 34.7 U/l, P = 0.004) and AST (-3.8 ± 12.9 vs. 0.4 ± 22.4 U/l, P = 0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT. CONCLUSION A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV-infected patients with abdominal obesity and elevated baseline transaminases.

Background Obesity and lipohypertrophy are common in treated human immunodeficiency virus (HIV) infection and contribute to morbidity and mortality among HIV-infected adults on antiretroviral therapy (ART). Methods We present a consensus opinion on the diagnosis, clinical consequences, and treatment of excess adiposity in adults with treated HIV infection. Results Obesity and lipohypertrophy commonly occur among HIV-infected adults on ART and may have overlapping pathophysiologies and/or synergistic metabolic consequences. Traditional, HIV-specific, and ART-specific risk factors all contribute. The metabolic and inflammatory consequences of excess adiposity are critical drivers of non-AIDS events in this population. Although promising treatment strategies exist, further research is needed to better understand the pathophysiology and optimal treatment of obesity and lipohypertrophy in the modern ART era. Conclusions Both generalized obesity and lipohypertrophy are prevalent among HIV-infected persons on ART. Aggressive diagnosis and management are key to the prevention and treatment of end-organ disease in this population and critical to the present and future health of HIV-infected persons.

Background: Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown. Objectives: The goals of this exploratory secondary analysis were to determine the effects of tesamorelin on muscle quality (density) and quantity (area). Design: Secondary, exploratory analysis of two previously completed randomized (2:1), clinical trials. Setting: U.S. and Canadian sites. Participants: People living with HIV and with abdominal obesity. Tesamorelin participants were restricted to responders (visceral adipose tissue decrease ≥8%).Intervention: Tesamorelin or placebo. Measurements: Computed tomography scans (at L4-L5) were used to quantify total and lean density (Hounsfield Units, HU) and area (centimeters2) of four trunk muscle groups using a semi-automatic segmentation image analysis program. Differences between muscle area and density before and after 26 weeks of tesamorelin or placebo treatment were compared and linear regression models were adjusted for baseline and treatment arm. Results: Tesamorelin responders (n=193) and placebo (n=148) participants with available images were similar at baseline; most were Caucasian (83%) and male (87%). In models adjusted for baseline differences and treatment arm, tesamorelin was associated with significantly greater increases in density of four truncal muscle groups (coefficient 1.56-4.86 Hounsfield units; all p

Between 2006 and 2017, frailty prevalence decreased in HIV-positive individuals aged 50 years but presented a 3-fold increase among those 75 years of age. This dynamic relationship, defined as the frailty compression ratio, represents the net result of gero-inducing and gero-protective competing forces, described in the cohort.

Long-term survival of treated people living with HIV (PLWH) currently approaches that of the general population. The average age of PLWH is currently in the mid-50s in resource-rich countries and is predicted that over 40% of PLWH will be older than 60 within a decade. Similar trends have been confirmed in all communities of PLWH with access to antiretroviral therapies. However, the positive impact on survival has been challenged by several developments. Ageing PLWH have clinical features similar to the general population about 5–10 years older. In addition to the earlier occurrence of common age-related conditions common geriatric syndromes have also impacted this population prematurely. These are often difficult to evaluate and manage conditions usually of multifactorial aetiology. They include polypharmacy, frailty, impaired mobility and falls, sarcopenia, sensory impairment, and increasingly, non-dementing cognitive decline. Cognitive decline is of particular concern to PLWH and their care providers. In the general geriatric population cognitive impairment increases with age and occurs in all populations with a prevalence of over 25% in people over 80. Effective treatments are lacking and therefore minimizing risk factors plays an important role in maintaining healthspan. In the general population geriatric syndromes may increase the risk of cognitive decline. The corollary is that decreasing the risk of their development may limit cognitive impairment. Whether a similar status holds in PLWH is uncertain. This chapter will address the question of whether common geriatric syndromes in PLWH contribute to cognitive impairment. Common risk factors may provide clues to limit or delay cognitive decline.

Frailty is an age-related syndrome of decreased physiological reserve and resistance to stressors, associated with increased morbidity and mortality in the general elderly population. An increased prevalence of frailty has been reported amongst HIV-infected individuals. Fried frailty phenotype was systematically assessed in predominantly virologically suppressed HIV type 1 (HIV-1)-infected and otherwise comparable HIV-uninfected participants aged at least 45 at enrollment into the AGEhIV Cohort Study. Multivariable ordinal logistic regression was used to investigate associations between HIV- and antiretroviral therapy-related covariates, markers of inflammation and body composition and prefrailty/frailty. Data were available for 521 HIV-infected and 513 HIV-uninfected individuals. Prevalence of frailty (10.6 versus 2.7%) and prefrailty (50.7 versus 36.3%) were significantly higher in HIV-infected individuals (Ptrend

Herpes zoster (HZ) occurs at a higher age-specific rate in people living with HIV (PLWH) than in the general population. We implemented a quality improvement study to assess herpes zoster vaccine (HZV) usage among PLWH, assess HZV usage after additional reminders/prompts, and identify barriers to HZV among older PLWH. HZV rates in PLWH were determined in six institutions with varying payment structures. For the intervention, Part 1, PLWH eligible for HZV at the University of Colorado were identified, and providers were notified of patient eligibility. In Part 2, in addition to provider notification, an order for HZV was placed in the patient's chart before a clinic appointment. HZ vaccination rates ranged from 1.5% to 42.4% at six sites. Before the intervention, 21.3% of eligible University of Colorado patients had received HZV. An additional 8.3% received HZV with Part 1 and 17.8% with Part 2 interventions. At completion, a total of 53.2% of eligible patients had received HZV through routine clinical care or the interventions. Insurance coverage concern was cited as a common reason for not receiving HZV. Minor adverse reactions occurred in 26.7% patients and did not require medical care. HZV coverage was low at a majority of sites. Clinical reminders with links to vaccination orders or preplaced vaccination orders led to improved HZV coverage in our clinic, but published guidelines for use of HZV in PLWH and improvement in logistic or insurance barriers to HZV receipt are paramount to improved HZV coverage.

BACKGROUND Initial declines in bone mineral density (BMD) after antiretroviral therapy initiation in HIV are well described, but data on long-term changes and risk factors for decline, particularly among women, are limited. METHODS HIV-infected men and women in the Modena Metabolic Clinic underwent dual-energy X-ray absorptiometry (DXA) scans every 6-12 months for up to 10 years (median 4.6 years). Mixed effect regression models in combined and sex-stratified models determined annual rates of decline and clinical factors associated with BMD. Models included demographics, HIV-specific factors, and bone-specific factors; a final model added a sex × time interaction term. RESULTS A total of 839 women and 1759 men contributed ≥2 DXA scans. The majority (82%) were 50 years and younger; 76% had HIV-1 RNA

The increased survival of treated people living with HIV (PLWH) represents a tremendous accomplishment. However, this has not been accompanied by uniform improvements in quality of life. Many PLWH prematurely develop age-related complications and traditional geriatric syndromes, including frailty. This is a potentially reversible state of vulnerability to adverse outcomes. Its operationalization remains challenging. The most commonly used tools, the frailty phenotype and the frailty index, have their advantages and limitations, but predict similar poor outcomes. Yeoh et al. applied both metrics, and a simpler construct, the Edmonton Frail Scale, to a population of Australian PLWH. Although the prevalence of frailty was generally similar to that in other settings, distinct differences occurred between the tools. This paper adds to the literature on this serious condition in this already vulnerable population. Further research is needed before consensus is reached on how to reliably and simply diagnose frailty in PLWH.

Background Late presentation (LP) at the time of HIV diagnosis is defined as presentation with AIDS whatever the CD4 cell count or with CD4

Background People aging with HIV show variable health trajectories. Our objective was to identify longitudinal predictors of frailty severity and mortality among a group aging with HIV. Methods Exploratory analyses employing a multistate transition model, with data from the prospective Modena HIV Metabolic Clinic Cohort Study, based in Northern Italy, begun in 2004. Participants were followed over four years from their first available visit. We included all 963 participants (mean age 46.8±7.1; 29% female; 89% undetectable HIV viral load; median current CD4 count 549, IQR 405-720; nadir CD4 count 180, 81-280) with four-year data. Frailty was quantified using a 31-item frailty index. Outcomes were frailty index score or mortality at four-year follow-up. Candidate predictor variables were baseline frailty index score, demographic (age, sex), HIV-disease related (undetectable HIV viral load, current CD4+ T-cell count, nadir CD4 count, duration of HIV infection, and duration of antiretroviral therapy [ARV] exposure), and behavioral factors (smoking, injection drug use (IDU), and hepatitis C virus co-infection). Results Four-year mortality was 3.0% (n = 29). In multivariable analyses, independent predictors of frailty index at follow-up were baseline frailty index (RR 1.06, 95% CI 1.05-1.07), female sex (RR 0.93, 95% CI 0.87-0.98), nadir CD4 cell count (RR 0.96, 95% CI 0.93-0.99), duration of HIV infection (RR 1.06, 95% CI 1.01-1.12), duration of ARV exposure (RR 1.08, 95% CI 1.02-1.14), and smoking pack-years (1.03, 1.01-1.05). Independent predictors of mortality were baseline frailty index (OR 1.19, 1.02-1.38), current CD4 count (0.34, 0.20-0.60), and IDU (2.89, 1.30-6.42). Conclusions Demographic, HIV-disease related, and social and behavioral factors appear to confer risk for changes in frailty severity and mortality among people aging with HIV.

prevention therapy. It is thus noteworthy that the available regimen for PrEP, the daily use of a fixed-dose combination of oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), contains tenofovir (TFV). TFV causes renal toxicity, via a proximal tubulopathy, and bone demineralization, by increasing bone turnover and altering bone metabolism, in a minority of patients [6]. In general, low bone mineral density (BMD) occurs more frequently in treated HIV adults than in seronegative individuals [7]. Low BMD is associated with an increased risk of fragility fractures [8, 9]. The etiology of low BMD is multifactorial, including both HIV- and cART-related factors [10], plus common causes of low BMD, as occurs in seronegative persons [11], including low body weight [12]. Currently available cART regimens are associated with a BMD decline of 4%–6%, generally occurring in the 4–6 months after starting treatment, and which is nonprogressive [10]. TFV-HAART is associated with greater BMD loss compared with non-TFV regimens [7]. Significantly, TFV-HAART has been associated with an increased fracture risk compared with other regimens in some studies [13]. In this context, Mulligan et al have

Objectives The accuracy of the use of anthropometrics to quantify visceral adipose tissue (VAT) in treated HIV-infected patients is unknown. We evaluated the predictive accuracy of waist circumference (WC) with and without dual-energy X-ray absorptiometry (DXA)-derived trunk : limb fat ratio [fat mass ratio (FMR)] as surrogates for VAT determined using computerized axial tomography (CT-determined VAT). Methods We performed a retrospective cohort analysis of treated HIV-infected male patients followed at the Modena HIV Clinic. We developed prediction equations for VAT using linear regression analysis and Spearman correlations. Receiver operating characteristic (ROC) analysis evaluated the accuracy of WC alone or with FMR at discrete VAT thresholds. Results The 1500 Caucasian male patients had a median age of 45 years, body mass index (BMI) of 24, WC of 87 cm, VAT area of 127 cm2 and body fat percentage of 14%. The correlation between WC-predicted VAT and CT-VAT was 0.613, and this increased significantly if FMR was added. The WC-associated R2 of 0.35 increased to 0.51 if the prediction equation included WC plus FMR. The area under the ROC curve (AUC) using WC was 0.795−0.820 at all VAT thresholds. The positive predictive value (PPV) and negative predictive value (NPV) changed reciprocally at CT-VAT thresholds from 75 to 200 cm2 and ranged from 0.72 to 0.74, respectively, at a representative VAT of 125 cm2. Adding the FMR to the predictive equations increased the AUC in the range of 0.854−0.889 with the PPV and NPV increasing minimally, ranging from 0.780 to 0.821. Limits of precision were wide, especially at the highest CT-VAT levels, and varied from 24 to 68 cm2. Conclusions WC is a limited surrogate for CT-VAT in this population and DXA-derived parameters do not improve performance indices to a clinically relevant level. These findings should inform the applicability of WC to predict VAT in treated HIV-infected male patients.

Skeletal fractures are more common in HIV, and impact the medical, functional and economic status of frequently vulnerable patients. Identifying asymptomatic patients with low bone mineral density (BMD)/osteoporosis requiring intervention can be expected to reduce fracture risk and complications. Clinical tools are available to determine fracture risk in the general population and are being evaluated in HIV patients. The FRAX calculator, incorporating demographics and risk factors for osteoporosis, with or without BMD results, has been investigated most often in HIV patients.The few published studies that have calculated the 10-year FRAX risk for both major osteoporosis and hip fractures without BMD generally show limited precision in predicting the presence of osteoporosis severe enough to initiate treatment. It remains uncertain whether using HIV as a secondary risk factor and adding dual X-ray absorptiometry (DXA)-BMD information improves case-finding compared with using DXA results only. Not incorporating risks relevant to aging HIV patients such as antiretroviral exposure, hepatitis C virus coinfection and history of falls is other potential limitation.Accurate screening tools using clinical risk factors alone to determine fracture risk in HIV are not yet available. Further research and validation studies are necessary.

The interaction between fall and fracture risk factors is an area of increasing clinical relevance, but little information is known about the age-specific issues in bone health unique to HIV-infected adults. The present review will focus on what is known about falls and fall risk factors among HIV-infected adults, and then review the association between decreased muscle, increased adiposity, and frailty with both low bone mineral density (BMD) and falls.The rate of falls among middle-aged HIV-infected adults is similar to that of HIV-uninfected adults 65 years and older. Many of the clinical factors that contribute to low BMD overlap with risk factors for falls, resulting in a high risk of a serious fall among older adults with the greatest risk for a fracture. Low muscle mass, increased adiposity and metabolic syndrome, physical function impairment and frailty, common among older HIV-infected adults, contribute to an increased risk for low BMD and falls, and subsequently, may increase the risk of fracture among HIV-infected older adults.Interventions with dual benefit on reducing fall risk and improving BMD are likely to have the greatest impact on fracture prevention in the older, HIV-infected adult.

Inflammaging describes the increase in inflammation-driven chronic illnesses that exist in older adults.

Metabolic toxicities in HIV patients are common and contribute to clinical status and long-term sequelae. Body fat mass alterations, of multifactorial causes, continue to occur, despite use of antiretroviral drugs associated with fewer metabolic side-effects. The role of HIV itself in the development of these changes is being better defined and a deeper understanding of perturbations in intermediary metabolic processes is emerging. Treatment options are also being identified.HIV itself may be a direct causal factor in the accelerated atherosclerosis and decreased levels of high-density lipoprotein that occur and contribute to increased cardiovascular complications. Antiretroviral drug-related and inflammation-related effects can cause mitochondrial toxicity and are an emerging area of research. The association of increased visceral adipose tissue with both drug-related and chronic inflammation-related factors is now better understood. The role of accelerated aging as a paradigm is useful to understand long-term outcome risks for patients. The use of growth hormone-releasing factor as a viable treatment option for increased visceral abdominal tissue has recently been confirmed for selected patients.Metabolic issues persist in HIV patients who are otherwise stable. Understanding the various inter-related contributing factors has allowed for rapid improvement in patients' clinical status, but long-term consequences are of concern and require ongoing investigation in order to prevent limiting the otherwise important clinical achievements that have recently occurred.

The percent fat in soft tissues adjacent to the lumbar spine and proximal femur, which are required parameters in the calculation of bone mineral by conventional dual-energy X-ray absorptiometry (DXA) of the spine and hip, were analyzed for their relationship with the total-body soft tissue-scanning derivatives. The cohort (N=149), consisting of stable actively treated male human immunodeficiency virus HIV-positive patients, was split in half to obtain prediction equations with one half to be validated by the other half. Prediction equations for the dependent variables total-body fat, total-body lean mass, trunk fat, total arm + leg fat, and leg fat were derived by step-down multiple regression. A Bland-Altman comparison of the predicted and observed values showed that the limits of agreement were too large to be clinically helpful. The correlations of the ratio of adjacent spine/hip fat with ratios of trunk/arm + leg fat and trunk/leg fat, markers of peripheral lipoatrophy in HIV, were 0.725 and 0.780, respectively. The 3 ratios were compared with the clinical diagnosis of the presence or absence of peripheral lipoatrophy by receiver operating characteristic analysis. The area under the curve was 0.720 for adjacent spine/hip fat ratio and 0.655 and 0.699 for trunk/arm + leg fat and trunk/leg fat, respectively; they were not significantly different. In conclusion, for male HIV-positive patients, the difference between predicted values and actual values rendered limits of agreement that were too wide to be clinically acceptable. The ratio of percent fat in the lumbar spine region to percent fat in the proximal femur region reflected the presence of peripheral lipoatrophy as effectively as the trunk/peripheral fat ratio that was derived from the total-body scan.

Increasingly effective therapies for HIV infection are now available. These treatments, referred to collectively as highly active antiretroviral therapy, comprise various combinations of anti-HIV drugs from different drug classes. Recently, a range of metabolic complications have emerged as important toxicities in treated patients. Complications present as abnormalities of body-fat mass distribution in association with an often significant dyslipidemia and glucose homeostasis dysregulation. The body-shape changes, manifesting as peripheral lipoatrophy or central lipohypertrophy, can have a negative impact on quality of life and consequently on adherence to treatment. The combination of central lipohypertrophy, dyslipidemia and insulin resistance is associated with accelerated rates of atherosclerosis and other potentially significant long-term effects. The pathogenesis of these effects is complex and is still being actively investigated. Possible contributing factors relate to host characteristics, HIV viral parameters and specific effects of anti-HIV drugs on adipose-tissue biology and on intermediary metabolism. Management of these complications involves manipulation of the anti-HIV drugs using an understanding of their particular effects on lipid and glucose metabolism, in association with standard therapeutic interventions. Individualized approaches, taking into consideration quality-of-life issues, and assessment of potential cardiovascular risks, are now an important component of effective care of HIV-infected patients.

Objectives Aging with HIV is associated with multisystem vulnerability that might be well characterized by frailty. We sought to construct a frailty index based on health deficit accumulation in a large HIV clinical cohort and evaluate its validity including the ability to predict mortality and incident multimorbidity. Design and methods This is an analysis of data from the prospective Modena HIV Metabolic Clinic cohort, 2004-2014. Routine health variables were screened for potential inclusion in a frailty index. Content, construct, and criterion validity of the frailty index were assessed. Multivariable regression models were built to investigate the ability of the frailty index to predict survival and incident multimorbidity (at least two chronic disease diagnoses) after adjusting for known HIV-related and behavioral factors. Results Two thousand, seven hundred and twenty participants (mean age 46 ± 8; 32% women) provided 9784 study visits; 37 non-HIV-related variables were included in a frailty index. The frailty index exhibited expected characteristics and met validation criteria. Predictors of survival were frailty index (0.1 increment, adjusted hazard ratio 1.63, 95% confidence interval 1.05-2.52), current CD4 cell count (0.48, 0.32-0.72), and injection drug use (2.51, 1.16-5.44). Predictors of incident multimorbidity were frailty index (adjusted incident rate ratio 1.98, 1.65-2.36), age (1.07, 1.05-1.09), female sex (0.61, 0.40-0.91), and current CD4 cell count (0.71, 0.59-0.85). Conclusion Among people aging with HIV in northern Italy, a frailty index based on deficit accumulation predicted survival and incident multimorbidity independently of HIV-related and behavioral risk factors. The frailty index holds potential value in quantifying vulnerability among people aging with HIV.

Background Tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) in human immunodeficiency virus (HIV)-infected patients with lipodystrophy. Objectives 1) To evaluate the utility of patient characteristics and validated disease-risk scores, namely indicator variables for the metabolic syndrome defined by the International Diabetes Federation (MetS-IDF) or the National Cholesterol Education Program (MetS-NCEP) and the Framingham Risk Score (FRS), as predictors of VAT reduction during tesamorelin therapy at 3 and 6 months, and 2) To explore the characteristics of patients who reached a threshold of VAT 1.7 mmol/L, and white race had a significant impact on likelihood of response to tesamorelin after 6 months of therapy (interaction p-values 0.054, 0.063, and 0.025, respectively). No predictive factors were identified at 3 months. The odds of a VAT reduction to

Objective: To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation. Design and methods: Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters. Results: TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo). Trunk fat decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. Visceral fat (VAT) decreased most in the 2 mg group (-5.4, -3.6 and -15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo. Subcutaneous fat (SAT) was preserved and did not change between or within groups. Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo. Treatment was generally well tolerated without changes in glucose. Conclusions: TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation. TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.